Rosacea is a common but poorly understood disorder of the facial skin that is estimated to affect well over 14 million Americans. Rosacea is characterized by flushing, erythema, papules, pustules, telanglectasia, facial edema, ocular lesions, and, in its most advanced and severe form, hyperplasia of tissue and sebaceous glands leading to rhinophyma. It may appear as redness, prominent spider-like blood vessels, swelling, or skin eruptions similar to acne. Rhinophyma, a florid overgrowth of the tip of the nose with hypervascularity and modularity, is an unusual progression of rosacea of unknown cause. Ocular lesions are common, including mild conjunctivitis, burning, and grittiness. Blepharitis, the most common ocular manifestation, is a non-ulcerative condition of the lid margins. One typically distinguishes between four common subtypes: (I) erythematotelangiectatic rosacea, (II) papulopustular rosacea, (III) phymatous rosacea, and (IV) ocular rosacea.
Flushing and the regulatory mechanism of the blood vessels are of importance in the pathogenesis of rosacea. The stages associated with flushing progress from episodes of flushing to persistent telangiectases. Telangiectasia, the dilation of capillaries and small blood vessels, has been studied using infrared photography and results have indicated, consistent with a previously developed theory that the color change in rosacea (i.e. skin appears red; also described as redness) is due to the dilation of the non-muscular endothelial capillaries and venules.
The symptoms of rosacea are exacerbated by sun exposure, hot weather, immersion in hot water, high humidity, sweating, exercise, emotional stress, spicy food, vasodilating stimuli, alcoholic beverages.
While the cause of rosacea is poorly understood, numerous theories have been offered. For example, such hypotheses have included gastrointestinal, psychological, infectious, climatic, and immunological causes. One commonly proposed etiologic theory is based on the presence of Demodex folliculorum mites in patients with rosacea. This organism feeds on sebum, and, in some cases, treatments of Demodex infestation have led to improvements in the rosacea. However, in a review of biopsies, Demodex folliculorum was noted in only few of the specimens. Likewise, a bacterial cause for the disease has also been hypothesized, but consistent findings of one bacteria have yet to be demonstrated.
Although climate, specifically exposure to extremes of sun and cold, may have an effect on the course of the disease, the exact role of climate is not clear. Similarly, while an autoimmune process has been suggested, and tissue fixed immunoglobulins have been reported in patients with chronic inflammation of rosacea, no other evidence has been found. Some other experimental evidence has suggested that rosacea may represent a type of hypersensitivity reaction.
Thus, as no single hypothesis appears to adequately explain both the vascular changes and the inflammatory reaction seen in patients with rosacea, the pathogenesis of this disease is unclear.
Rosacea and rosacea treatments and potential therapies have been extensively described in numerous review articles such as Scheinfeld et al., A review of the diagnosis and treatment of rosacea. Postgrad Med 122:139-43 (2010); Webster, Rosacea. Med. Clin North Am 93:1183-94 (2009); Kennedy Carney et al., Rosacea: a review of current topical, systemic and light-based therapies. G Ital Dermatol Venereol 144: 673-88 (2009); Culp et al., Rosacea: A review. P&T 34:38-45 (2009); Barco et al., Rosacea. Actas Dermosifiliogr 99: 244-56 (2008); Van Zuuren et al., Systematic review of rosacea treatments. J Am Acad Dermatol 56:107-15 (2007); Buechner, Rosacea: an update. Dermatology 210:100-108 (2005); and Bikowski et al., Rosacea: where are we now? J Drugs Dermatol 3:251-261 (2004).
Currently, treatment for rosacea can be orally or topically applied antibiotics (such as tetracycline, clindamycin, erythromycin), as well as vitamin A, salicylic acid, zinc oxide, antifungal agents, or steroids. Another known treatment for rosacea is metronidazole (an antiprotozoal and antibacterial agent) and permethrin (a pyrethroid), alone or with oral 13-cis-retinoic acid (isotretinoin). (See Signore, Cutis, 56: 177-79 (1995)). Metronidazole, however, has been reported as ineffective against skin redness, telangiectases and flushing.
Drugs useful for inhibiting flushing include, for example, methysergide, indomethacin, clonidine, aspirin, promethazine, propranolol, diazepam, and cimetidine. (See Guarrera, et al., Arch Dermatol Res, 272:311-16 (1982)). In addition, U.S. Pat. No. 5,952,372 discloses a method of treating rosacea with oral or topical use of ivermectin, and U.S. Pat. No. 5,932,215 discloses the use of Calcitonin Gene Related Peptide (CGRP), a substance P antagonist, in compositions to treat skin redness in discrete erythema and rosacea.
Frequently, the skin of a patient suffering from rosacea is hypersensitive, and therefore, the treatment for rosacea is or feels particularly irritating to the skin. In fact, most patients with rosacea complain of sensitive skin that stings, burns, and itches after application of treatment compositions, cosmetics, fragrances, or sunscreens because their facial skin is unusually vulnerable to chemical and physical stimuli. (See Plewig, G. and Kligman, A. M., “Acne and Rosacea”, p. 435 (2d ed. 1993)). Soaps, alcoholic cleansers, tinctures and astringents, abrasives and peeling agents are all potential irritants and should be avoided.
Therefore, reducing irritation associated with compositions designed to treat rosacea is a special problem. Even more difficult to treat, is the irritation experienced when treating the skin for rosacea complexed with acne vulgaris. Typically, products are formulated to be free of irritating ingredients such as actives, surfactants emulsifiers, and fragrances. However, when this approach is taken, there can be a compromise in the efficacy of the ingredients with respect to their desired activity.
Accordingly, there is a need for compositions suitable for topical application and methods for treating this disease that are efficient, well-tolerated or non-irritating, are stable, and do not cause an acnegenic/comedogenic response. The compositions and methods of the present invention address these long felt needs in the art.